This research program is directed towards an understanding of the neurophysiological, neurochemical, and behavioral correlates of the decline in spatial cognition with age, and the development of preventative and/or ameliorative treatments for this decline. The investigations focus on aging of the rodent hippocampal system, and its major cortical and subcortical connections. Aged animals are deficient in the retention of long-term enhancement of hippocampal synaptic transmission (which is currently a strong candidate mechanism for associative memory storage); furthermore, there is a break down, with age, in the specificity and reliability of spatial information processsing by single neurons in the aged hippocampus. The proposed experiments will continue the study of the mechanisms of age-changes in synaptic modifiability and their relation to memory decline and will investigate possible means of altering this decline. In order to gain a more complete understanding of the neurobiological basis of spatial cognitive changes with age, a detailed study is proposed of the neurophysiology and neuropharmacology of other major afferent and efferent systems of the hippocampus, beginning, in the present proposal period, with the cholinergic septo-hippocampal projection. This projection is strongly implicated both in spatial memory and in the regulation of information processing in the hippocampal formation leading to place specificity in the discharge pattern of its single neurons. Three approaches will be taken to this problem: 1) investigation, by means of electrically evoked field potentials in conscious animals, of changes in septal facilitation of hippocampal postsynaptic excitability and the modulation by this pathway of synaptic enhancement; 2) neuropharmacological analyses of changes in postsynaptic responsiveness (recorded both extracellularly and intracellularly) of nicotinic and muscarinic cholinergic agents applied by microiontophoretic methods both in vivo and in vitro; 3) examination of age influences on spontaneous unit activity and local circuit interactions in medial septal nucleus during performance of behavioral tasks designed for the analysis of spatial cognition, using a technique for simultaneous recording of multiple single units in behaving animals recently developed in this laboratory.